Quaternary ammonium salts of nu-phenyl-nu-picolyl-dialkylaminoalkylamines



QUATERNARY AMlVlONIUlVI SALTS OF N-PHEN- IYL-N-PICOLYL-DIALKYLAMINOALKYLAMINES Robert R. Burmer, Skokie, Ill.,assignor, by mesne assignments, to G. D. Searle & Co., Skckie, Ill., acorporation of Delaware No Drawing. Application March 30, 1953, SerialNo. 345,670

7 Claims. (Cl. 260-296) This invention relates to quaternary ammoniumsalts of N-phenyl-N-picolyldialkylaminoalkylamines, and to processes forthe preparation thereof. In particular, this invention relates topicoline derivatives of the forwherein Alk is a lower alkylene radicalcontaining at least two and not more than four carbon atoms; R is alower alkyl radical, that is, a radical containing not more than 4carbon atoms; NRR" is either a lower dialkylamino radical or anitrogen-containing heteromonocyclic radical; and X is one equivalent ofan anion.

In the compounds of the foregoing formula, Alk represents an alkyleneradical such as ethylene, propylene, butylene, trimethylene,tetramethylene, and like bivalent radicals derived from saturatedaliphatic hydrocarbons containing from 2 to 4 carbon atoms. The radicalR represents a lower alkyl radical such as methyl, ethyl, propylisopropyl, butyl, isobutyl, and secondary butyl. The radicals R and R"represent lower alkyl radicals of the foregoing type; or, taken togetherwith the attached nitrogen, they represent saturated,nitrogen-containing, heterocyclic radicals such as piperidino,morpholino, and pyrrolidino radicals. The substituent X represents oneequivalent of an anion, as remarked, and includes such non-toxicanionsas chloride, bromide, iodide, methyl sulfate, ethyl sulfate,benzenesulfonate, toluenesulfonate, tartrate, succinate, malate,acetate, citrate, nitrate, su fate, phosphate, sulfamate, and the like.

The compounds of this invention are useful in medicine asanticholinergic agents. They have the property of blocking thetransmission of nerve impulses across the autonomic pulse transmissionat the neuroefiector junctions of the parasympathetic and cerebrospinalnervous "systems. Thus the quaternary ammonium salts of this inventionare capable of producing the chemical equivalent of sympathectomy, thesurgical interruption of some portion of the sympathetic nervouspathways.

Because of their ability to block the autonomic ganglia, the instantcompounds are valuable in the control of ulcer and othergastrointestinal dysfunctions associated with autonomic hyperactivity.In this respect they are distinct from the corresponding tertiary basesand their simple addition salts, the activity of which is largelylimited to the neuroefiector junctions of the parasympathetic system.The latter compounds are commonly classified as spasmolytics inrecognition of this essential difference between their properties andthose which charganglia, as well inhibiting n'ervedm such as a nitrogenatmosphere, is

acterize the anticholinergic agents of the present invention.

The subject compounds are soluble in water, as also in aqueous solutionsof alcohols and water-miscible organic solvents. They may beadministered in solid form as tablets or capsules; dissolved in aqueousmedia they may be given parenterally.

The compounds to which this invention relates are conveniently preparedaccording to the following procedure: An a halogenated picoline, forexample, a 2-- bromopicoline, is reacted with aniline in the presence ofa condensing agent such as potassium carbonate or, preferably, copperpowder, to form an N-phenyl-N-apicolylamine. The condensation isordinarily carried out at elevated temperatures to 175 centigrade) andreduced pressures (25 to 60 millimeters of mercury) vover periods oftime ranging upward from one hour.

One suitable combination of temperature, pressure, and time is tocentigrade at 40 millimeters pressure for six hours. Thephenylpicolylamine is, in turn, reacted successively with a condensingagent, such as sodamide, and a dialkylaminoalkyl halide, for examplediethylaminoethyl chloride, to produce the correspondingN-phenyl-N-u-picolyldialkylaminoalkylamine. Various inert, non-polar,organic liquids will serve as reaction media, toluene having been founda solvent of choice When sodamide is the condensing agent. Withpotassium carbonate, methyl ethyl ketone may be used. The reaction iscommonly run at temperatures of 90 to 110 Centigrade and completed afterapproximately 20 hours. Temperatures of the order of 20 higher or lowermay also be used, and the reaction time may vary from 10 to as long as36 hours. An inert atmosphere, ordinarily maintained throughout thecourse of the reaction, though this may be dispensed with after thefirst 2 or 3 hours. The N- phenyl-N-a-picolyldialkylaminoalkylamine thusformed, the formula of which is RI! where Alk, R and R have the meaningshereinbefore defined, is then quaternized by addition of an alkyl esterof the formula 24 hours.

The following examples will illustrate in detail cerrain of the picolinederivatives which constitute the present invention, and methods whichhave been devised for their preparation. However, the invention is notto be construed as limited therebyeither in spirit or in scope, since itwill be apparent to those skilled in the art of organic synthesis thatof materials and of methods,

may be practiced without departing from the purpose Patented Mar. 5,1957 The remany modifications, t both and intent of this disclosure. Inthe examples hereinafter detailed, temperatures are 3 given, in degreescentigrade 0.), pressures in millimeters (mm.) of mercury, and relativeamounts of matenals in parts by weight, except as otherwise noted.

EXAMPLE 1 A. N-(6-methyl-2-pyridyl)-N-phenylamine.-A mixture of 344parts of 2-bromo-6-methylpyridine, 186 parts of aniline, and parts ofcopper powder is heated in a jacketed vessel at 140 to 150 C. (jackettemperature) and an absolute pressure of 40 mm. of mercury for 6 hours.An excess of 10% aqueous muriatic acid is added, whereupon the copper isfiltered out and the reactants then made alkaline with an excess of 25%aqueous caustic soda. The base, thus precipitated as an oil, isextracted into ether. The ether solution is washed with water, followingwhich the solvent is stripped, and the residue is then subjected tovacuum distillation. The distillate, a pale yellow oil, B. P. 180-l82 C.at 8 mm. pressure, is the desired product.

B. N-(6-methyl 2 pyridyl) -N phenyldiethyl-aminoethylamine.--To astirred suspension of 63 parts of sodamide in 2700 parts of dry tolueneat 90-100 C. under an atmosphere of nitrogen is added 298 parts of N-(6--methyl2-pyridyl)-N-phenylamine. The reactants are refluxed and stirredfor approximately 3 hours, at the end of which time heating isdiscontinued and 217 parts of diethylaminoethyl chloride is slowlyadded. An exothermic reaction ensues, following which heat is againapplied and reflux continued for hours. Approximately 3000 parts ofwater is then added, whereupon the toluene layer is, successively,separated, washed with water, and subjected to vacuum distillation toremove the solvent. The dark viscous oil which remains is the desiredN-(G-methyl 2 pyridyl)-N-phenyldiethylaminoethylamine. It may beconverted to the hydrochloric acid salt by dissolving in 3400 parts ofanhydrous ether and treating with two molecular equivalents of absolutealcoholic hydrogen chloride solution. The salt is isolated by decantingthe supernatant ether-alcohol layer, taking up the residue in 13 volumesof a mixture of 1000 parts of isopropyl alcohol and 4500 parts of ethylacetate at the boiling point, and then allowing the solution to cool andstand at C. The dihydrochloride comes out as white crystals which,recovered on a funnel and dried at 75 C., melt at 192 C. The product ismoderately hygroscopic and easily soluble in water.

C. N-(6 methyl 2 pyridyl) N-phenyldiethylaminoethylamine meth0br0mide.Asolution of 320 parts of N- (6-methyl-2-pyridyl) -N-phenyldiethylaminoethylamine and 107 parts of methyl bromide in 1500 parts of drychloroform is allowed to react in a closed system for 24 hours at 25 C.The solvent is then distilled oil, leaving a viscous residue which istaken up in 4000 parts of anyhydrous ether. The crystalline quaternarycompound forms on standing. It is filtered ofi, rinsed with ether, andfinally dried at 75 C. The product is obtained as white crystals, M. P.130-131" C., and is readily soluble in water. It has the formula EXAMPLE2 A. N-(4-luethyl-2-pyrirlyl)-N-phenylamine.-A mixture of 344 parts of2-bromo-4-methylpyridine, 186 parts of aniline, and 10 parts of copperpowder is heated in a jacketed vessel at 140-150 C. (jacket temperature)and an absolute pressure of 40 mm. of mercury for 6 hours according tothe technique of Example 1A. The mixture, which refiuxes gently duringthe first hour, gradually becomes more viscous and ceases reflux as thereaction progresses. At the end of the prescribed heating period, thereactants are acidified with approximately 6700 parts of 10% aqueousmuriatic acid, filtered, and made alkaline with an excess of 25% aqueouscaustic soda, in that order. The base so precipitated g'ranulates onstanding, and is thereupon filtered out and, successively, ground andwashed with water, dried, and finally recrystallized from 1900 parts ofcyclohexane to give nearly white plates, M. P. 119 C.

B. N-(4-methyl 2 pyridyl) N phenyldierhylam'inoethylamine.Usingessentially the procedure of Example 1B, 177 parts ofN-(4-methyl-2-pyridyl) N-phenylamine, 38 parts of sodarnide, and partsof diethylaminoethyl chloride in 2600 parts of dry toluene are reactedat reflux temperatures for 20 hours to give, in good yield, the desiredN-(4-methyl 2 pyridyl) N- phenyl'diethylaminoethylamine as an oil. Thebase may be converted to the dihydrochloride' by reaction in anhydrousether solution with two molecular equivalents of absolute alcoholichydrogen chloride solution. The salt comes down as a viscous oil whichgranulates on standing. Recrystallization from 10 volumes of a mixtureof 23 parts of isopropyl alcohol and 110 parts of ethyl acetate gives,following treatment with decolorizing charcoal, colorless crystals, M.P. l95l96 C. The dihydrochloride is quite soluble in water.

C. N-(I-mathyl-Z-pyrialyl)-N-phenylaliethylaminaethyiamine methylbromide-A solution of parts of N- (4methyl-2-pyrid-yl-N-phenyldiethylaminoethylamine and 48 parts of methyl bromide in 7500parts of chloroform is stored in a closed container for 24 hours at 25C., at theend of which time the bulk of the solvent is removed by vacuumdistillation and. 2500 parts anhydrous ether is then added to theviscous residue. The product, which becomes crystalline on standing, isrecrystallized from 6 volumes of. a mixture of 16 parts of isopropylalcohol and 72 parts of ethyl acetate to give, on treatment withdecolorizing; charcoal, nearly colorless crystals, M. P. 164 C. Theproduct, which is readily soluble in water, has the formula EXAMPLE 3 A.N-(4-methyl-2-pyridyl) -N-phenyl-B-dimethylamiiwpropylamine.-Thesecondary amine of the preceding Example 2A is converted to the tertiaryfi-dimethylaminopropylamine according to the following procedure: partsof N-(4-methyl 2-pyridyl)N-phenylamine, 39 parts of soda'mide, and 122parts of ,o-dimethylaminopr'opyl chloride in 2700 parts of dry tolueneare reacted as described in Example 13. There results a good yield ofN-(4-me'thyl 2 pyridyl) N -phenyl-3-dimethylaminopropylamine which,treated in anhydrous ether solution with two molecular equivalents ofabsolute alcoholic hydrogen chloride solution, gives thedihydrochloride.

B. N-(4-melhyl-2-pyridyl)-N-phenyl-B-dimethylaminopropylamine eth'yli0dide.-The tertiary base of the preceding Example 3A is quaternized asdescribed in Example lCby reacting 255 parts thereof together with 170parts of ethyl iodide, in 1500 parts of dry chloroform. Upon removal ofsolvent and addition of ether, the deabout hours. discontinued while 250parts of B-di-n-butylaminopropyl chloride is slowly added, followingwhich heat is again :applied and reflux continued with stirring for 24hours.

Approximately 4000 parts of water is then added, wheremove the solvent.

sired product is obtained as a viscous oil which granulates on standing.It has the formula CHzCHCHs EXAMPLE 4 A. N-(6-methyl-2-pyridyl)-N-phenyl-B-di-n-butylaminopropyIamine.-To a stirred suspension of 39parts of sodamide in 3500 parts of benzene at reflux temperature under anitrogen atmosphere is added 170 parts of N-(6-methyl-Z-pyridyl)-N-phenylamine prepared according to the directions ofExample 1A. The reaction mixture is maintained at reflux temperaturewith stirring until evolution of ammonia gas ceases, which is usuallyafter At this point, heating is temporarily upon the benzene layer is,successively, separated, washed with water, and subjected to vacuumdistillation to re The residual dark, viscous oil is the desiredproduct. It may be converted to the hydrochloric acid salt bydissolution in 3000 parts of anhydrous ether and subsequent reactionwith two molecular equivalents of absolute alcoholic hydrogen chloridesolution according to the technique of Example 1B. The dihydrochlorideis quite soluble in water.

B. N-(6-methyl-2-pyridyl)-N-phenyl-fl-di-n-butylaminopropylamine ethylsulfate.A mixture consisting of 339 parts of the base of Example 4A, 154parts of diethyl sulfate, and 1500 parts of anhydrous butanol is main- 1tained at 50 C., with stirring, for 30 hours. The quaternary ammoniumcompound so prepared has the formula v6 I claim: 1. A compound of theformula wherein Alk is a lower alkylene radical containing at least twoand not more than four carbon atoms; R is a lower alkyl radical; NRR" isa member of the group consisting of lower dialkylamino, pyrrolidino,morpholino, and piperidino radicals; and X is one equivalent of anon-toxic anion.

2. An N-phenyl-N-picolyldialkylaminoethylamine quaternary salt of theformula N CHzOHz-N X RI! wherein R, R and R are lower alkyl groups and Xis halogen.

3. An N-phenyl-N-picolyldialkylaminoethylamine methobromide of theformula References Cited in the file of this patent UNITED STATESPATENTS 2,406,594 Djerassi et al Aug. 27, 1946 2,479,843 Knox et a1.Aug. 23, 1949 2,502,151 Horclois Mar. 28, 1950 2,623,880 Hopfi et a1Dec. 30, 1952 OTHER REFERENCES Idson: Chem. Reviews, vol. 47 (Dec. 1950)pp. 341-44, 377-79, 462-66, 470-73, 477-79, 505-08.

1. A COMPOUND OF THE FORMULA